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Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients

2015; BMJ; Volume: 52; Issue: 10 Linguagem: Inglês

10.1136/jmedgenet-2015-103218

1468-6244

María Currás-Freixes, Lucía Inglada‐Pérez, Veronika Mančíková, Cristina Montero‐Conde, Rocío Letón, Iñaki Comino‐Méndez, María Apellániz-Ruiz, Lara M. Munín Sánchez, Miguel Aguirre Sánchez-Covisa, Victoria Alcázar, Javier Aller, Cristina Álvarez‐Escolá, Víctor M Andía-Melero, Sharona Azriel-Mira, María Calatayud-Gutiérrez, José Ángel Díaz, Alberto Díez-Hernández, Cristina Lamas, Mónica Marazuela, Xavier Matías‐Guiu, Amparo Meoro-Avilés, Ana Patiño‐García, Susana Pedrinaci, Garcilaso Riesco‐Eizaguirre, Constantino Sábado, Raquel Sáez-Villaverde, Amaya Sainz de los Terreros, Óscar Sanz Guadarrama, Júlia Sastre-Marcos, Bartolomé Scolá-Yurrita, Ángel Segura-Huerta, Maria de la Soledad Serrano-Corredor, María Rosa Villar-Vicente, Cristina Rodríguez‐Antona, Esther Korpershoek, Alberto Cascón, Mercedes Robledo,

Cancer, Hypoxia, and Metabolism

Background Nowadays, 65–80% of pheochromocytoma and paraganglioma (PPGL) cases are explained by germline or somatic mutations in one of 22 genes. Several genetic testing algorithms have been proposed, but they usually exclude sporadic-PPGLs (S-PPGLs) and none include somatic testing. We aimed to genetically characterise S-PPGL cases and propose an evidence-based algorithm for genetic testing, prioritising DNA source. Methods The study included 329 probands fitting three criteria: single PPGL, no syndromic and no PPGL family history. Germline DNA was tested for point mutations in RET and for both point mutation and gross deletions in VHL , the SDH genes, TMEM127 , MAX and FH . 99 tumours from patients negative for germline screening were available and tested for RET , VHL , HRAS , EPAS1 , MAX and SDHB. Results Germline mutations were found in 46 (14.0%) patients, being more prevalent in paragangliomas (PGLs) (28.7%) than in pheochromocytomas (PCCs) (4.5%) (p=6.62×10 −10 ). Somatic mutations were found in 43% of those tested, being more prevalent in PCCs (48.5%) than in PGLs (32.3%) (p=0.13). A quarter of S-PPGLs had a somatic mutation, regardless of age at presentation. Head and neck PGLs (HN-PGLs) and thoracic-PGLs (T-PGLs) more commonly had germline mutations (p=2.0×10 −4 and p=0.027, respectively). Five of the 29 metastatic cases harboured a somatic mutation, one in HRAS . Conclusions We recommend prioritising testing for germline mutations in patients with HN-PGLs and T-PGLs, and for somatic mutations in those with PCC. Biochemical secretion and SDHB-immunohistochemistry should guide genetic screening in abdominal-PGLs. Paediatric and metastatic cases should not be excluded from somatic screening.